MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production
MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production
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DOI：
10.4161/epi.2.4.5212
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发表时间：
2007-10-01
期刊：
影响因子：
3.7
通讯作者：
Shemer, Ruth
中科院分区：
文献类型：
--
作者：
Abuhatzira, Liron;Makedonski, Kirill;Shemer, Ruth
BDNF基因的表达中断，其编码参与神经元存活、分化和突触可塑性的神经营养因子，已被提出有助于Rett综合征的分子发病机制。Rett综合征（RTT）是一种神经发育障碍，由X连锁甲基CpG结合蛋白2基因（MeCP2）突变引起。脑中MeCP2缺乏已显示降低BDNF的总体表达，尽管观察到启动子III的活性增加，其似乎直接由MeCP2控制。因此，MeCP2缺陷如何导致BDNF表达的整体下调是一个谜。在这里，我们报告说，在人类和小鼠大脑中的MeCP2缺乏导致两个神经元基因转录抑制因子REST（RE1沉默转录因子）和CoREST的表达增加。MeCP2结合并参与Rest和CoRest启动子的抑制，尽管它们处于未甲基化状态。MeCP2消耗与组蛋白修饰谱向更活跃构象的变化相关。RTT患者和MeCP2缺陷小鼠脑中REST和CoREST水平升高导致BDNF下调，显然是通过它们与位于BDNF基因前两个启动子之间的RE 1（元件）结合。有趣的是，编码BDNF受体TRKB的NTRK2基因在MeCP2缺陷的人类和小鼠大脑中直接过表达或试图补偿BDNF缺陷。
Disruptions in the expression of the BDNF gene that encodes a neurotrophic factor involved in neuronal survival, differentiation and synaptic plasticity has been proposed to contribute to the molecular pathogenesis of Rett syndrome. Rett syndrome (RTT) is a neurodevelopmental disorder, caused by mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 deficiency in the brain has been shown to decrease overall expression of BDNF in spite of an observed increase in the activity of promoter III that appears to be controlled directly by MeCP2. Therefore, how MeCP2 deficiency causes an overall downregulation of BDNF expression was an enigma. Here we report that MeCP2 deficiency in human and mouse brain causes an increase in expression of two neuronal gene transcriptional repressors REST (RE1 silencing transcription factor), and CoREST. MeCP2 binds to and is involved in repression of Rest and CoRest promoters despite their unmethylated state. MeCP2 depletion is associated with a change in the histone modification profile to a more active conformation. The elevated levels of REST and CoREST in the brain of RTT patients and MeCP2 deficient mice result in downregulation of BDNF, apparently by their binding to the RE1 (element) located between the first two promoters of the BDNF gene. Interestingly, the NTRK2 gene that encodes the BDNF receptor, TRKB, was overexpressed in MeCP2 deficient human and mouse brains either directly or as an attempt to compensate for BDNF deficiency.